Conventional diagnostic tests are performed on humans to evaluate the amount or existence of analytes in the blood, which requires drawing of a blood sample. Typically, blood samples are removed from a subject either by using a syringe or by pricking the skin. This involves pain and inconvenience, and may cause patients to miss monitoring routines. One blood/body analyte of interest is blood glucose with quantitative analysis done using enzymatic method with Glucose Oxidase (GOx). The amount of blood drawn, of course, depends upon the amount of blood required for testing. Thereafter, the blood sample may be prepared and specifically tested for a variety of substances using techniques well known in the art. To overcome the problems associated with the invasive techniques, several approaches have been proposed that involves collection/extraction of analytes through the skin/biological membrane by enhancing its permeability.
Several techniques are employed to enhance the permeability of the biological membrane, such as creating physical micropores, physically disrupting the lipid bilayers, chemically modifying the lipid bilayers, physically disrupting the stratum corneum, and chemically modifying the stratum corneum. The creation of micropores, or the disruption thereof, may be achieved by physical penetration, using a heat source, an ultrasonic needle, an ultrasonic transducer, cryogenic ablation, RF ablation, photo-acoustic ablation, a needle, a microneedle, a laser, and combination thereof.
Although these methods can be used for extraction of body fluids, there are certain limitations that may apply when applied to human skin. For example, a major limitation is the flow and volume of body fluid that can be transported across the stratum corneum. In general, high-pressure force is necessary in order to transport fluid across an enhanced permeable area of stratum corneum. The application of vacuum on skin for an extended period may cause physical separation of the epidermis from the dermis result in bruises and blisters.
Over the last few years, methods of determining the concentration of blood glucose or other substances without drawing blood have been developed. For example, Stanley U.S. Pat. No. 5,139,023 describes a transdermal glucose monitoring apparatus that uses a permeability enhancer, such as a natural bile salt, to facilitate transdermal movement of glucose along the concentration gradient between the higher glucose concentration in the interstitial fluid and the lower glucose concentration in the receiving medium. In some embodiments, the receiving medium is the aqueous portion of a hydrogel support adhered to the subject's skin. Stanley measured the glucose concentration within the hydrogel by removing the hydrogel from the subject's skin, placing the hydrogel in water and letting the glucose diffuse out of the hydrogel into the water. The water was then analyzed for glucose concentration.
Sembrowich U.S. Pat. No. 5,036,861 describes a glucose monitor that collects the subject's sweat through a skin patch attached to the subject's wrist.
Sembrowich describes the use of iontophoresis to transdermally introduce a gel into the subject's skin. The gel contains a cholinergic agent for stimulating the secretion mechanism of the eccrine sweat gland and agents that minimizes or prevents loss of glucose from the sweat as it travels from the sweat gland to the skin patch.
The Sembrowich device uses electrodes to measure the glucose level in the collected sweat by some unspecified method.
Schoendorfer U.S. Pat. No. 5,076,273 describes a method and apparatus for determination of chemical species in body fluid. Sweat expressed from the subject's skin is collected in a patch adhered to the subject's skin. The patch concentrates the sweat in a binder layer by driving off a portion of the collected water. The collected analyte binds with a specific binding partner in the patch to present a visual indication of its presence in the patch.
Schroeder U.S. Pat. No. 5,140,985 discloses a sweat-collecting device mounted on a subject. The device has an electrode-based glucose detection system that can give a qualitative indication of blood glucose concentration.
Glikfeld U.S. Pat. No. 5,279,543 describes the use of iontophoresis to sample a substance through skin into a receptor chamber on the skin surface. In one embodiment, Glikfeld describes an in vitro device consisting of two gel electrodes attached to one side of hairless mouse skin. Radiolabeled glucose is placed on the other side of the skin, and current is applied to the electrodes for a period of time. The electrodes are then analyzed for radioactivity content by conventional liquid scintillation counting.
In general, non-invasive analyte detection systems known in the literature have limitations in withdrawal/extraction of targeted body fluids in desired quantities and thereby have detection accuracy/reliability related issues and often their detection response time is unacceptably slow. For these reasons, non-invasive analyte detection methods for therapeutic purposes have not yet become commercially viable.
For example, iontophoresis and variety of individual energy forms (including an array of microneedles) have been used to transport the body fluid across the skin membrane involving multitude of transport mechanisms. However each energy form has its own preferred transport mechanism and may have limitations with regard to the quantity, and type of fluid they could extract across the skin membrane. Besides the fluid permeation rates dramatically vary depending upon the nature of energy form applied. In this regard, we propose the use of a single controller that provides a combination of energy sources/pulses to act upon a transdermal patch (which may include microneedles) with varying intensity, sequence, and timing to enable the transport of fluids using synergistic/cooperative transport mechanisms. As a consequence, application of multiple energy forms in a predetermined sequence/time intervals and intensities provides an excellent opportunity to permeate body fluids containing analytes in adequate quantities rapidly, and thus provide precise control over the analyte detection. It is also possible to pull the analytes of interest selectively along with the body fluids by permeating suitable counter ions with Iontophoresis. Further, the extraction of body fluids through multiple energies could be complemented by application of a negative pressure/vacuum for enhancing detection accuracy.
In this venture, we take advantage of printed electronics/microneedle arrays to extract and/or collect body fluid transdermally using a combination of transport mechanisms and energy sources, i.e., heat, sound and electromotive force, where a microprocessor controls the thermal/ultrasonic energy and electrical current applied to the skin in a programmable fashion (concurrently or alternately) for body fluid extraction and detection applications. A modified version of the transdermal patch system reported here could be used for transdermal drug delivery across the skin, while using a similar controller that provides combination of energy sources (Patent No: 819/CHE/2010, An Active Transdermal Drug Delivery and The Method Thereof). One such interest is transdermal delivery of Insulin.
Further, the disclosure is intended to generate a new versatile active transdermal patch for extracting a variety of analytes along with body fluids with controlled transportation rates and quantities to enable on demand detection of the analytes. Current active transdermal non-invasive patches rely on unregulated or inadequate quantities of body fluids that impose several limitations on accurate detection of analytes in prescribed/required time intervals for reliable medical diagnostics of practical utility.